Bioeffecting agentsxe2x80x94agents which engage in a biological activity or are effective in modulating a biological activityxe2x80x94are often applied to the surface of articles for a variety of purposes. For example, bath mats are often sprayed with agents containing benzalkonium salts to inhibit the growth of microbes. Bioeffecting agents are also used to alter the surface properties of the materials to which they are applied. A pharmaceutical preparation of heparin when applied to a medical device provides its surfaces with antithrombogenic properties.
To prolong the duration of the bioeffecting activity or to delay its initiation, bioeffecting agents have been encapsulated or embedded in materials for subsequent release in particular locations or under particular conditions. For example, polyglycolic and polylactic acids have found significant usage as resorbable biomaterials and have often been blended during processing to include a variety of bioeffecting agents. The bioeffecting agents contained in these materials are released as the products degrade. The rate of delivery of the agents is determined by the local conditions which affect the diffusion of the bioeffecting agents and the degradation of the enclosing materials. Bioeffecting agents have also been incorporated in materials such as hydrogels which swell in moist environments. Hydrogels release the agents through diffusion into the local environment.
Various types of chemical attachments have been employed to bind bioeffecting agents to articles in attempts to improve the duration of the bioeffecting activity. A number of ionic bonds have been used, because bioeffecting agents possessing sufficient ionic charge can be readily attached to the surfaces of articles containing the opposite ionic charge. Hsu, for example, in U.S. Pat. No. 4,871,357, describes an ionic heparin coating for use with medical devices. The release of materials which are attached to substrates with ionic bonds is governed both by the strength and number of the ionic pairs, and by local conditions such as pH and moisture. Ionic bonds disassociate quite rapidly under moist conditions. Even ionic systems of attachment designed to include protectants against wet environments tend to be less durable under those conditions. Ionic attachment can also adversely affect the function of bioaffecting materials during the period of attachment.
Covalent bonds, relying on a number of functional groups, have been used to attach bioeffecting agents to the surface of articles. In U.S. Pat. No. 4,810,784, Larm described a method of covalent attachment using glutaraldehyde and aldehyde conversions, while Burns utilized a method of attachment relying on carbodiimide conversion in U.S. Pat. No. 5,527,893. Guire, in U.S. Pat. No. 5,336,579, described a method which used a combination of isocyanate and photo-activation hydrogen abstraction. While these types of bonds provide good attachment of the agent to the article, they can be difficult and complicated to form on the surface of the substrate, often requiring multiple modifications. In addition, the final covalent bond formed is not generally reversible, and the bioaffecting activity of the agent is often altered significantly by its interaction with the functional group providing the attachment.
The present invention is based, at least in part, on the discovery of a multicomponent complex for reversibly attaching bioeffecting agents to substrates so that the agents may be released over an extended period of time while still retaining the capacity for substantial bioeffecting activity. The invention provides compositions and methods for use with substrates which are useful in the sustained delivery of bioeffecting agents. The compositions of the invention include a multicomponent complex which attaches a bioeffecting agent to a substrate with an anchor provided by a linker compound which also forms a cleavable linkage so that the bioeffecting agent""s release into the area surrounding the substrate occurs in a sustained manner over an extended period of time. The methods of the invention involve providing a bioeffecting composition or the surface of a substrate so that a bioeffecting agent may be released in a sustained manner over time. Accordingly, the compositions and methods of the invention are useful for delivering bioeffecting agents to a localized area where their sustained release permits bioeffecting activity to occur over an extended period of time.
The present invention pertains to a combination of a multicomponent complex for delivering a bioeffecting agent for use with a substrate and an article. The combination includes a complex for delivering a bioeffecting agent for use with a substrate and for delivering a bioeffecting agent having a bioeffecting domain component, a segment component containing at least two linking domains, and an anchoring moiety component. Accordingly, the multicomponent complex can have the formula:
[Q]-[S]-[T]
where Q is a bioeffecting domain component; S is a segment component containing at least two linking domains; and T is an anchoring moiety component; and the components are selected such that a cleavable linkage anchored to the substrate is formed which sustains the release of the bioeffecting agent over time. The combination contains an article which is in contact with the complex. In one preferred embodiment, the article is a medical device adapted for in vivo uses.
The present invention also provides a multicomponent complex for delivering a bioeffecting agent for use with a substrate having a bioeffecting domain component, a segment component containing at least two linking domains, and an anchoring moiety component. Accordingly, the multicomponent complex can have the formula:
[Q]-[S]-[T]
where Q is a bioeffecting domain component; S is a segment component containing at least two linking domains; and T is an anchoring moiety component and the components are selected such that a cleavable linkage anchored to the substrate is formed which sustains the release of the bioeffecting agent over time.
The present invention also provides a composition for delivering a bioeffecting agent for use with a substrate. The composition contains a multicomponent complex for delivering a bioeffecting agent for use with a substrate having a bioeffecting domain component, a segment component containing at least two linking domains, and an anchoring moiety component. Accordingly, the multicomponent complex can have the formula:
[Q]-[S]-[T]
where Q is a bioeffecting domain component; S is a segment component containing at least two linking domains; and T is an anchoring moiety component and the components are selected such that a cleavable linkage anchored to the substrate is formed which sustains the release of the bioeffecting agent over time. The composition contains a solution in contact with the complex.
The present invention further pertains to packaged compositions for delivering a bioeffecting agent for use with a substrate. A packaged composition includes a container holding a compound supplying at least one component of a multicomponent complex for delivering a bioeffecting agent for use with a substrate having a bioeffecting domain component, a segment component containing at least two linking domains, and an anchoring moiety component. Accordingly, the multicomponent complex can have the formula:
[Q]-[S]-[T]
where Q is a bioeffecting domain component; S is a segment component containing at least two linking domains; and T is an anchoring moiety component and the components are selected such that a cleavable linkage anchored to the substrate is formed which sustains the release of the bioeffecting agent over time. The packaged composition contains instructions for using the composition to deliver a bioeffecting compound.
The present invention also provides methods for providing a sustained release bioeffecting coating on the surface of an article by applying a coating solution to a surface of the article such that a layer containing the sustained release bioeffecting coating is formed upon the article surface, such that the formed layer contains a multicomponent complex containing a bioeffecting domain component, a segment component containing at least two linking domains, and an anchoring moiety component, the components selected such that a cleavable linkage anchored to the substrate is formed, and the release of the bioeffecting domain is sustained over time.